An analysis of veterans diagnosed with large granular lymphocytic disorders at the national Veteran Affairs Healthcare System
Authors: Helen Ma, Thomas P. Loughran, Pankaj Gupta
Journal: American Journal of Hematology (2023)

Large granular lymphocytic (LGL) leukemia is an uncommon lymphoproliferative disorder characterized by a clonal expansion of greater than 0.5 × 109/L circulating neoplastic T cells (CD3+CD8+ and either CD57+ or CD16+) or NK cells (CD3-CD8+CD16+ and/or CD16+CD56+).1 There is an association with STAT3 mutations and inflammation caused by autoimmune diseases, such as rheumatoid arthritis and pure red cell aplasia (PRCA), as well as chronic viral infections, such as hepatitis B and hepatitis C.1, 2 Treatment consists of immunosuppression and is reserved for patients with the following indications: (1) severe neutropenia, defined as an absolute neutrophil count (ANC) <0.5 × 109/L, (2) moderate neutropenia (ANC >0.5 × 109/L) with recurrent infections, (3) symptomatic or transfusion dependent anemia, and (4) autoimmune conditions necessitating therapy. Methotrexate has been used as first line therapy due to its efficacy in both LGL leukemia and comorbid conditions, that is, rheumatoid arthritis. In the setting of PRCA, cyclophosphamide has been recommended because of higher response rates (6/8 patients responded) compared to cyclosporine A or prednisolone.2 Military exposures may be associated with the development of lymphoid malignancies, but an association has not been well described in LGL leukemia. Herein we describe the characteristics and outcomes of patients diagnosed with LGL leukemia (30% of whom potentially had military exposures) and managed in the national Veteran Affairs (VA) Healthcare System. This is a retrospective, secondary analysis of electronic health records of a VA cohort of patients diagnosed with LGL leukemia from January 1, 1998 to December 31, 2020 using the VA informatics infrastructure.3 The VA is the largest integrated healthcare system in the United States with sites also in American Samoa, Guam, Philippines, Puerto Rico, and the Virgin Islands. The diagnosis of LGL leukemia was made by the detection of monoclonal population of at least 0.5 × 109/L cells with the expression of CD3+CD8+CD16+/−CD57+/− and a T-cell receptor gamma gene rearrangement as T-cell LGL leukemia, and CD3-CD16+CD56+ as NK-cell LGL leukemia. If the LGL cell count was <0.5 × 109/L by peripheral blood flow cytometry, then this was deemed to be precursor state. Transformation was defined as an aggressive progression of disease with lymphocytosis. Descriptive data summarized patient and disease characteristics. Treatments were categorized as methotrexate-based, cyclophosphamide-based, cyclosporine A-based, growth factors, or other immunosuppression, which included steroids and mycophenolate. Response rates were evaluated by blood counts and organ response after four 28-day cycles of therapy. A complete response (CR) was defined as improvement of hemoglobin >11 g/dL, platelets >100 × 109/L, ANC >1.5 × 109/L, and lymphocyte count <4 × 109/L; a partial response defined as improvement in counts without meeting CR, stable disease as no response within 4 months, and progressive disease (PD) as worsening cytopenias or organomegaly.4 Multivariate hazard ratios were calculating with the Cox proportional hazard model. Overall survival (OS) was defined as the time from date of diagnosis to death from any cause. Disease specific survival (DSS) was defined as the time from date of diagnosis to death from hematologic malignancy. Patients who were alive were censored at the date of last contact (data cutoff December 31, 2020). Kaplan–Meier curves were used to estimate survival and compared by log-rank tests. Causes and dates of death were confirmed by using data from the National Death Index through December 31, 2020.5 p-values were reported for two-sided tests. This study was approved by the Institutional Review Boards at the VA Long Beach Healthcare System and the University of California, Irvine and was conducted in accordance with the principles of the Declaration of Helsinki. From 1998 through 2020, 280 patients were identified with LGL leukemia. Seventeen were identified to have a precursor LGL leukemia. Almost half were diagnosed by peripheral blood flow cytometry (n = 139), the other half diagnosed by bone marrow biopsy (n = 138) precluding calculation of absolute circulating LGL cell count. The method of diagnosis was unknown for seven patients. Median time from diagnosis to initiation of treatment was 0.8 months (range, 0–100 months). A minority of patients underwent next generation sequencing, and eight patients were found to have a STAT3 mutation. Supplementary Table 1 summarizes patient characteristics. Notably, 28% of patients had at least one military exposure, almost 20% of patients were exposed to Agent Orange (AO), 10% to combat, very few were exposed to Southwest Asia theater of conflict, Camp Lejeune, and none to ionizing radiation. Supplementary Table 2 summarizes patient management with the time to treatment within 1 month, 1–6 months, 6–12 months, and over 1 year calculated as 90 (32%), 50 (18%), 6 (2%), and 20 (7%) patients, respectively. In AO exposed patients, the median OS and DSS were 8.7 years (95% confidence interval [CI], 6.2-not reached [NR]) and NR (95% CI, NR-NR) compared to 7.0 years (95% CI, 6.1–9.0) and NR (95% CI, NR-NR) for AO unexposed patients, respectively (Figure 1A,B). For the overall cohort, the median OS and DSS were 7.4 years (95% CI, 6.5–9.1) and NR (95% CI, NR-NR), respectively (Supplementary Figure 1A,B). Notably, patients with LGL leukemia were more likely to die from other causes (67%) than their hematologic malignancies (33%); causes of death are summarized in Supplementary Table 3. On univariate analysis, anemia with hemoglobin (HGB) <11 g/dL, having another cancer, and increasing age were statistically significantly associated with worse survival, but race, branch of military, tobacco use, ANC <1.5 × 109/L, thrombocytopenia with platelet (PLT) less than 100 × 109/L, autoimmune disease, AO exposure, combat exposure, and viral infections were not. On multivariate analysis, anemia with HGB <11 g/dL (HR 1.776, 95% CI 1.179–2.674), having another cancer (HR 1.43, 95% CI 1.002–2.052), and increasing age at diagnosis (HR 1.052, 95% CI 1.028–1.077) remained statistically significantly associated with worse survival. Median OS of patients who presented with ANC <1.5 × 109/L, HGB <11 g/dL, or PLT <100 × 109/L compared to patients who had higher blood counts were 7.1 years (6.3–17.5) versus 7.4 years (95% CI, 6.1–9.2), p = .412, 4.9 years (95% CI, 4.3–6.8) versus 8.7 years (95% CI, 7.1–17.5), p < .0001, and 6.2 years (95% CI, 4.2–9.2) versus 7.4 years (95% CI, 6.5–9.4), p = .364, respectively (Supplementary Figure 2A–C). Median DSS of patients with ANC <1.5 × 109/L, HGB <11 g/dL, or PLT <100 × 109/L compared to patients with higher blood counts were NR (95% CI, NR-NR) in both, p = .058, 11.2 (95% CI 11.2-NR) versus NR (95% CI, NR-NR), p < .0001, NR (95% CI, NR-NR) in both, p = .999, respectively (Supplementary Figure 2D–F). Our data are consistent with several large retrospective cohorts of similar size in that patients with LGL leukemia have an excellent median DSS.6 Our population was predominantly male and older with the median age of diagnosis of 70 years compared to the other reports where the median age of diagnosis was 65 (range, 17–90) and there was more equal distribution between genders.6 About half of veterans had enlisted in the army, 2/3 had a history of tobacco use, and 1/3 had known military exposures. Even with our mostly male cohort, our data support the association of autoimmune disease with LGL disorders.6 A small proportion of patients were exposed to specific military exposures, limiting analysis on their impact on outcomes. Over half of patients were monitored as first line of therapy. Since many underwent diagnostic work up for cytopenias, about a third of patients started treatment within 1 month of diagnosis in the VA system. In our veteran population and consistent with the literature, anemia (HGB <11 g/dL) has been shown to be associated with worse survival6 whereas neutropenia and thrombocytopenia did not seem to impact survival. Our data show that 40% of veterans with LGL disorders also have a second malignancy, which is consistent with published data.6 There are case reports of patients with T-cell LGL leukemia who present with transformation based on an acute onset of systemic B symptoms, organomegaly, cytopenias, and lymphoadenopathy.7 Our study had two patients who had a similar course. This entity may be underreported and warrants further investigation. Limitations of this secondary analysis of a national VA medical record system include systemic error, selection bias, incomplete data, inconsistent documentation, and heterogeneous data quality. The national VA electronic medical record was established in 1999, and there may be different clinical outcomes in patients diagnosed prior to consistent electronic health documentation. There may be unknown confounding variables that bias the analysis. The classification of lymphoid malignancies has also changed several times in the past 20 years, potentially changing how diagnoses were categorized. In conclusion, exposure to AO did not seem to adversely impact survival. Even with a predominantly male population, the incidence of autoimmune disease was similar to reports of civilian patients with balanced gender distributions. Because of the severity of cytopenias at diagnosis, half of patients required treatment within 6 months. This historical cohort did not have routine next generation sequencing, which may be beneficial to better understand the biology and inform future treatment strategies. Veterans with LGL leukemia, managed at the VA have excellent outcomes, consistent with published reports. Helen Ma conceived the idea, collected the data, performed statistical analysis, wrote, and edited the manuscript. Thomas P. Loughran and Pankaj Gupta contributed clinical expertise and critically edited the manuscript. Helen Ma is a Lymphoma Research Foundation Lymphoma Scientific Research Mentoring Program scholar and recipient of a VA Career Development Award (1-IK2 CX002437-01A1). Helen Ma and Pankaj Gupta have no competing interests to report. Thomas P. Loughran is a member of Scientific Advisory Board and consultant for Keystone Nano, Dren Bio, Kymera Therapeutics, Recludix Pharma, and Prime Genomics. This study was approved by the Institutional Review Boards at the VA Long Beach Healthcare System and the University of California, Irvine and was conducted in accordance with the principles of the Declaration of Helsinki. Data S1. Supporting Information. 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